Phenylaminopropandiols



Patented Jan. 23, 1951 Harry M. Crooks, Jr., Mildred G. Rebstock, JohnControulis, and Quentin 3.. Bartz, Detroit, Mich., assignors to Parke,Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing.Application February 12, 1949, Serial-No. 76,173

Claims.

This, application is a continuation-in-part of our copending applicationSerial No. 15,264, filed March 16, 1948, now U. S; Patent 2,483,884,.and

the invention relates to new chemical compounds.

and to chemical methods. useful for their synthesis. More particularly,the. invention relates to. a new class of organic amino diols. and theiracid addition salts and to methods for. obtaining these products. Theamino diol compounds of the invention in their free base formcan berepresented by the formula,

where R1 and R2 are the. same or different and represent hydrogen,halogen, lower alkyl and lower alkoxy radicals and R3 is hydrogen or alower alkyl radical.

It will be appreciated by those skilled in the art that the amino diolsof the invention and the starting materials used in their preparationcan exist in structural as Well as optical isomeric forms. The termstructural isomer or form as used herein refers to the cis or trans,that, is, the planar relationship of the polar groups on the twoasymmetric carbon atoms. To difierentiate between these two possiblediastereoisomers we will subsequently refer to the cis compounds as theregular [reg] series or form and to the trans diastereoisomers as thepseudo [ll 1 series of form. Such cis compounds. are products whereinthe two most highly polar of the groups on the asymmetric carbon atomslie on the same side of the plane of the two carbon atoms. Conversely,the trans or pseudo compounds are those wherein the two most highlypolar groups lie on opposite sides of the plane of the two carbon atoms.

Both the regular and pseudo forms exist as racemates of the opticallyactive dextro [d] and levo [l] rotatory isomers as Well as in, the formof the individual or separated dextro [d] and levo [1] optical isomers.

Because of the difiiculty of representing these structural diiferencesin graphic formulae the customary structural formulae will be used inboth, the specification and claims, and a notation placed below or tothe side of the formula to.-.

designate the particular structural and optical configuration of thecompound. Where the formula represents the unresolved mixture of thestructural and optical isomers the notation unresolved will be used.However, it should be expressly understood that. where no notationappears with a structural formula the formula should be interpreted inits-generic sense,,thatr is, as representing the [ll-1p, [d], 11 -reg;or. [dl-reg. isomers in separated form as well as the [dl] or [dll-reg.optical racemates, orthe; total unresolved. mixture of structural andop.- tical isomers. Such a formula does not merely represent. theunresolved mixture of isomers.

The products of the invention may be prepared.

by. several different methods. One method. of

preparing these products consists in hydrolyzing;

an acylated amino diol having the; formula,

where R1v and R2 arethe same or' difierent and: represent hydrogen,halogen, lower alkylor lower alkoxy radicals, Raishydrogen ora. loweralkylradical and Brand R5. are the same or different andrepresenthydrogen or acyl radicals. The: term acyl as used hereinincludes saturated and' conditionscanbe used; However, we prefer to"hydrolyze using: dilute mineral acid since. it is mor efiicient inbringing about hydrolysisin a When acidic hydrolytic conditionsshortertime. are' used the-phenyl amino dio1'productis-present' inthe reactionmixture in the form of" an acid addition salt and it can eitherisolated. inthisform or it canbe neutralizedand isolated asthe freebase.

If desired, the hydrolysismay be carried out.

3 in a medium containing a water miscible organic solvent such asmethanol, ethanol, dioxane, npropanol and the like.

The reaction may be effected over a wide temperature range but ispreferably carried out at the boiling point of the reaction mixture.Some specific examples of the hydrolytic catalysts or reagents which canbe employed are hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide,lithium hydroxide, barium hydroxide, sodium carbonate, potassiumcarbonate and the like.

As stated above, the acid addition salts of the amino diols may beprepared directly by hydrolysis. These salts may also be prepared byreaction of the free base with the corresponding organic or inorganicacid. Some examples of these acid addition salts are the hydrochloride,

hydrobromide, hydroiodide, sulfate, sulfamate,

oxalate, tartrate, citrate, benzoate, maleate, succinate, acetate andthe like.

The amino diol products of the invention can also be produced byreduction of the corresponding nitro diol compound. 'Such nitro diolcompounds have the formula,

R OH N02 De R2 R3 Unresolved where R1, R2 and R3 have the samesignificance as given above. Due to the lability of the nitro groupthese nitro diol starting materials always exist in the unresolved stateand hence no attempt is made to separate them into their individualstructural and optical isomers prior to reduction. The amino diolproducts obtained by reduction are stable and can be, if desired,separated into their structural isomers by fractional crystallizationeither after or during the isolation of the amino diol from the reactionmixture. Each of these separated structural isomers of the amino diolscan be resolved further, if desired, into their component opticalisomers via an optically active acid addition salt of such acids as theoptically active camphor sulfonic acids, tartaric acids, mandelic acids,brom-camphor sulfonic acids-and the like. Neutralization of theoptically active salts after separation by fractional crystallizationfrom water and/ or organic solvents such as methanol, ethanol and ethylacetate yields the desired individual structural and optical isomer ofthe amino diol free base.

The reduction of the nitro diols is preferably accomplished by catalyticmeans using catalysts and conditions which do not cause hydrogenolysisof benzyl alcohol. Some of the catalysts which have been found suitablefor this purpose are palladium oxide, palladium on carbon and Raneynickel. When the foregoing hydrogenation catalysts are used thehydrogenation can be carried out under hydrogen pressures varying fromatmospheric, about lbs. per sq. in., to about 2000 lbs. per sq. in. andat temperatures ranging from about to 50 C. As media for thehydrogenation a variety of different organic solvents, such as acetic,acid and lower aliphatic alcohols, may be used.

Another method of effecting this transforma- 4 such as by the use ofreducing salts or acid-metal combinations. Some of the reducing saltswhich may be used are stannous chloride, sodium hydrosulfite, ferroussulfate and the like while ironacetic acid and zinc-sulfuric acid areexamples of the metal-acid reductants. Still another metal-acidcombination which has proved advantageous is a nickel-aluminum alloy,such as Raney nickel catalyst powder, in combination with acetic acid.

The amino diols of the invention and their acid addition salts arevaluable intermediates for the preparation of other organic compounds.They are of particular value as intermediates in the preparation oforganic compounds possessing antibiotic activity. For example, [1]-1-piodophenyl-2-aminopropane-l,3-diol, one of the products of Example9, can be converted by dichloroacetylation to [l] 1, 1 p iodophenyl-2-dichloroacetamidopropane 1,3 diol, a product possessing a high degree ofantibiotic activity. Similarly, the products of the invention havin thepseudo structural form, no substituents in the phenyl ring and athree-carbon side chain can be completely acylated, nitrated, hydrolyzedto the nitrophenyl amino diol, resolved via an optically active acidaddition salt, if necessary, to obtain the [llt-nitrophenyl amino dioland dichloroacetylated to obtain [1]-1-p-nitrophenyl -2-dichloroacetamidopropane -1,3- diol, a compound possessing an extremelyhigh degree of unique antibiotic activity.

The invention is illustrated by the following examples.

Example 1 [a] 20 g. of the sodium salt of l-phenyl-Z-nitropropane-1,3-diol is dissolved in 200 cc. of glacialacetic acid.0.75 g. of palladium oxide hydrogenation catalyst is added and themixture shaken with hydrogen under three atmospheres pressure for abouttwelve hours. removed by filtration, the filtrate concentrated I toabout one-tenth volume in vacuo and diluted tion consists in reducingthe l-phenyl-Z-nitrowith five volumes of water. The solution isextracted with one volume of ethyl acetate or ether and the extractdiscarded. The aqueous phase ismade alkaline to pH 12 with strong sodiumhydroxide solution and extracted with five cc. portions of ethylacetate. The combined extracts are dried, the ethyl acetate evaporatedto obtain the desired unresolved 1-pheny1-2-aminopropane-1,3-diol offormula,

Unresolved Crystallization of the unresolved 1-phenyl-2-aminopropane-1,3-dio1 from chloroform yields the [dll-reg. isomer ofl-phehyl-Z-aminopropane-1,3-diol; M. P. 103-4 C. This product has theformula,

OH NH: Ode-drmomon [fin-Reg. Form Evaporation of the chloroform filtrateafter separation of the [dll-reg. isomer followed by fractionalcrystallization of the residue from meth- The catalyst is rpropane-1,3-diol, of formula,

leam...

[6114 Form [(11] 4,0 Form By substituting an equivalent amount of [d1]-ip-l-phenyl-Z-benzamidopropane-1,3-diol for the N-acetyl derivative usedin the above procedure, one obtains the same product.

4 g. of [d1] ber-phenyla-acetamido-3- acetoxypropane-l-ol in 25 cc. of 3N hydrochloric acid is refluxed for about three hours and the reactionmixture evaporated to dryness. The residual hydrochloride salt is-takenup in a small amount of water, the solution made alkaline with sodiumhydroxide and extracted with ethyl acetate. After drying, the ethylacetate-is evapoe rated from the extracts in vacuo to obtain the freebase of [d1]-rp-l-phenyl-Z-aminopropane- 1,3-diol; M. P.- 81-3f Thisproduct has the formula,

OH NHz QCJ'H-(QH-CEHOH [an-1p Form [d] 3 g. of the triacetateofldll-ip-l-phenyl-2- aminopropane-lB-diolis heated with 100 cc. of 5%hydrochloric acid for two hours on a steam bath. The reaction mixture isevaporated to dryness in vacuo, the hydrochloride salt of [d1]--1-phenyl-2-aminopropane-1,3-diol thus obtained taken up in a smallamount of water and the solution made alkaline to pH 10.-with sodiumhydroxide. The solution is extracted with ethyl acetate, the combinedextracts dried and the ethyl acetate distilled in vacuo to obtain thedesired [dl]-r//-1-phenyl-2-aminopropane-1,3-diol of formula,

OH NH:- O-H-JJH-CHQOH [rill-1,0 Form If desired, 100 cc. of 5% sulfuricacid can be substituted for the hydrochloric acid used in the aboveprocedure.

[e] 4 g. of [d1]--1ephenyl-2 aminopropane 1,3-diol is dissolved in about60 cc. of warm nbutanol containing an equivalent amount of"- Edl-camphorsulfonic acid. The mixture is cooled and the crystalline [d]-camphorsulfonatesalt of [l] 11-1-pheny1-2-aminopropane-1,3-dioly1-2-aminopropane-1,3edi0lr is dissolved in a small amount of watercontaining an excess. ofv sodium hydroxide. The solution is extractedwith ethyl acetate, the ethyl. acetate extracts. dried and the solventdistilled in vacuo. The residue consists of l] u-1-phenyl-2-aminopro1.pane-1.,3-.-.diol which has the formula,

OH: NH2.

Basification of the [dl-camphor sulfonate: salt of['dl-xp-1-phenyl-2-aminopropane-1,3-diol yieldsthe desired Edl-d-isomerof the amino diol. By substituting[d1]-reg.-l-phenylez-aminopropane-L3-diol for the [dll-ip-amino diolusedin the above procedure one obtains the [d] and" [ll-reg. opticalisomers of 1phenyl-2-aminopropane-1,3-diol.

[f] 5 g. of [dll-reg.-1'-pheny1-2-aminoproe pane-1,3-diol is dissolvedin Water and treated with an equivalent amount of [dl-tartaric acid. Thereaction mixture, is evaporated to dryness and the mixture of the[dl-tartaric acid salts of the [d] and [1] forms ofreg-l-phenyl-Z-amindpropane-1,3-diol separated by fractionalcrystallization from absolute ethanol.

The [dl-tartaric acid salt of [d]-reg.-1-phenyl-2-aminopropane-.1,3-diolis dissolved in water, the solution made alkaline to pH 10 with sodiumhydroxide and extracted with ethyl acetate. The extracts are dried andthe ethyl acetate distilled to obtain the free base of[d]-reg.-l-phenyl-2- aminopropane-1,3-diol of formula,

OH NH:

an as l-Reg. form tained by decomposing the corresponding [d]- tartaricacid salt with sodium hydroxide.

[y] 1 g. of [1] --1-phenyl-2-aminopropane- 1,3-diol dissolved in a smallamount of isopropanol is added to a warm isopropanol solution containingone equivalent of oxalic acid monohydrate. The resulting mixture isevaporated to dryness in vacuo and the crystalline acid oxalate salt of[1]-\//-l-phenyl-2-aminopropane-1,3-diol purified by recrystallizationfrom isopropanol'.

0.5 g. of [l]--1-phenyl-2-aminopropane-l,3- diol is added to an aqueoussolution containing one equivalent of citric acid and the mixtureevaporated to dryness in vacuo. The citrate salt of [l] 11-1-phenyl-2-aminopropane-1,3-diol thus obtained is purified by recrystallizationfrom absolute alcohol.

0.5 g. of [d1]-1/1-1-phenyl-2-aminopropane-l,3- diol is dissolved in adilute solution of acetic acid and the, resulting solution evaporated todryness in vacuo to obtain the acetate salt of [all] Mil-1-phenyl-2-aminopropane-l,3-dio1.

l g. of [dl]-reg.-1-phenyl-2-aminopropane- 1,3-diol is dissolved ina-smallamount of alcohol and the resulting solution addedto a methanolsolution containing one equivalent of racernic tartaric acid. Theracem-ic; tartrate salt of [(111-- Example 2 [a] 18 g. of the sodiumsalt of l-o-methylphenyl-2-nitropropane-1,3-diol is dissolved in 175 cc.of glacial acetic acid, 0.75 g. of palladium oxide hydrogenationcatalyst added and the mixture hydrogenated under three atmospherespressure of hydrogen for about twelve hours. The catalyst is removed byfiltration, the filtrate concentrated to a small volume in vacuo andthen the residue diluted with five volumes of water. The solution isextracted with one volume of ethyl acetate or ether and the extractdiscarded. The aqueous phase is made alkaline to pH 12 with strongsodium hydroxide solution and extracted with five volumes of ethylacetate. ethyl acetate extracts are combined, dried and the ethylacetate evaporated in vacuo. The residue which consists of a mixture ofthe [dll-reg. and [d1] 41-1-o-methylphenyl-2-aminopropane- 1,3-diol istaken up in and crystallized from chloroform to obtain the[,dll-reg-l-o-methylphenyl-2-aminopropane-1,3 -diol in crystalline form.Its formula is,

OH NH:

an-Reg. form The chloroform filtrate from which the [d1]-reg.-l-o-methylphenyl-2-aminopropane-1,3 diol has been removed isevaporated in vacuo to obtain the crude [dl] 4/ l-o-methylphenyl-2-aminopropane-l,3-diol of formula,

OH NH:

QdHAtH-cmmr (GD-ill Form [b] 4 g. of[d1]-\//-1-o-methylphenyl-2-benzamidopropane-l,3-dio1 is heated with amixture consisting of 50 cc. of ethanol and 50 cc. of hydrochloric acidfor about two hours. The reaction mixture is evaporated to dryness invacuo, treated with about 125 cc. of water and the solution madealkaline to pH 10 with sodium hydroxide. The mixture is extracted withethyl acetate, the ethyl acetate extract washed with water, dried andevaporated to dryness in vacuo. The product thus obtained is[dll-rp-l-o-methylphenyl-2-aminopropane-l,3-diol of formula,

OH NHZ 7 (dB-W Form The.

'[cl 5 gfof [d1]-reg.-1-o-methylphenyl-2-dichloroacetamido 3benzoyloxyp'ropane l-ol is heated under reflux with 100 cc. of 5%hydrobromic acid for about four hours. The reaction mixture isevaporated to dryness in vacuo, the residue treated with 100 cc. ofwater and the resulting mixture made alkaline to pH 10 with sodiumhydroxide. The solution is extracted with ethyl acetate, the ethylacetate extract washed with water, dried and the ethyl acetate distilledin vacuo to obtain the, desired[d1l-reg.-1-omethy1phenyl-2-aminopropane-1,3-diol of formula,

.Ql laam I 1H3 (db-Reg. form Example 3 [a] 20 g. of the sodium salt ofl-m-methoxyphenyl-Z-nitropropane-1,3-diol is dissolved in 200 cc. ofglacial acetic acid. 0.75 g. of palladium oxide hydrogenation catalystis added and the mixture hydrogenated under three atmospheres pressureof hydrogen for about twelve hours. The catalyst is removed byfiltration, the filtrate concentrated in vacuo to about one-tenth of itsoriginal volume and the residue diluted with five volumes of water. Thesolution is extracted with ethyl acetate and the vextract discarded. Theaqueous solution is made alkaline to pH 12 with strong sodium hydroxide,extracted with ethyl acetate and the combined extracts dried. The ethylacetate is removed by distillation in vacuo to obtain the unresolvedl-m-methoxyphenyl- 2-aminopropane-1,3-diol of formula,

OH NH:

' Qdn-en-cmon CH3 1 I H .Unresolved formula of this product is,

' OH NH:

[(11] -Reg. form 11, and consisting of an aqueous solution contain- Thecorresponding [(11] -1-m-methoxypheny1- 2-aminopropane-L3-diol whichremains dissolved in the chloroform solution from the crystallization ofthe [dll -reg. isomer is recovered by evaptractwashed with water, driedand the. ethyl 'ligroin mixture yields the desired [dll --1- [3';4'--

9 acetate distilled in vacuo to obtain the desired [d1] 1/ 1 n1methoxyphenyl- 2 aminopropane-1,3-diol of formula,

Example 4 [a] A mixture consisting of g. of the sodium salt of1-[3.,4"-dimethy1phenyll-2-nitropropane-1,3-diol, 175 cc. of glacialacetic acid and 0.75 g. of palladium oxide hydrogenation catalyst isshaken under three atmospheres pressure of hydrogen for about fifteenhours. The catalyst is removed by filtration and the filtrateconcentrated to about one-tenth volume in 'vacuo. The residue is dilutedwith five volumes of Water, the solution extracted With one volume ofethyl acetate and the extract discarded. The aqueous solution is madealkaline 'to about pH 12 with sodium hydroxide, extracted with ethylacetate and the combined extracts dried. The ethyl acetate is evaporatedin vacuo to obtain the unresolved 1- [3' ,4 -dimethylphenyl] -2-aminopropane-1,3-diol of formula,

CH. :H-JJH-CHgOH Unresolved The unresolved 1- ['3' ,4'--dlmethylphenylfl'2- =aminopropane-1,3-diol is taken up in and crysta Evaporation of thechloroform filtrate after separation of the {dB-reg. isomer followed bycrystallization of the residue from ethyl acetate- 'di-methylphenyll-2aminopropane-1;3- diol of for- "mula,

OH NHz solved in a sma'll-amount of Water and treated with an excess ofsodium 'l'lydroxide.

The solution is extracted with ethyl acetate, the ethyl"acetateextracts-dried and the solvent disti led 10 dimethylphenyll-2-aminopropane-1,3-diolof tormula,

cm-Qdn-drpcmon [1110 Form The [d] -brorn-camphor sulfonate salt of[Cu-JP- 1 [3,4dimethylphenyl] 2 aminopropane 1,3-diol can be recoveredfrom the filtrates and neutralized with sodium hydroxide to obtain thedesired [011- 0-1-[3,4-dimethylphenyl]-2-aminopropane-1,3-diol offormula,

.[dl-L Form omQdnJJn-cmon on v [d1]-Reg. form Example :5

.[al 20 g. of the sodium salt of 2-n-itro-3-phenylbutane-1,3diol isdissolved in 200 CC."Of glacial acetic'acid, 0.75 g. of palladium oxidehydrogenation catalyst added to the solution and-the mixture shakenunder three atmospheres pressure of hydrogen for about fifteen hours.The "catalyst is removed by filtration and the filtrate :concentrated toone-tenth volume in vacuo. The residue is diluted With five volumes ofWater, the

- solution extracted with one volume of ethyl acetate and the extractdiscarded. The aqueous solution is made alkaline with sodium hydroxide[pH 12] and extracted with ethyl acetate. After drying, the ethylacetate is evaporated in vacuo from the combined extracts to obtain thedesired 2-amino-3-phenylbutane-1,3-diol of formula,

Unresolved If desired, this product can be separated into its regularand pseudo structural forms by crystallization from chloroform. The [d1]-reg.-2- amino-3-phenylbutanel,3-dio1 is the insoluble isomer.

lb] 3 g. of [dl]-reg.-2-aminoa3-nitrophsnylbutane-1,3-diol is added :toan absolute alcohol solution containing-an equivalent amount of :fdl...tartaric acid. The reaction:mixtureris-evaponated to-dryness in vacuoand the residue fractionally crystallized from absolute alcohol toobtain the [d] -tartaric acid salts of the individual [d] and [ll-reg.isomers of Z-aminO-S-phenylbutane-1,3- diol. The [d] -tartaric acid saltof the [(11 -reg. isomer which is the first to crystallize from themixture is dissolved in water containing an excess of sodium hydroxide.The solution is extracted with ethyl acetate, the extract dried and theethyl acetate distilled to obtain the desired [d]-reg.-2amino-3-phenylbutane-1,3-diol of formula,

[d]-Reg. form 1 Example 6 a] 50 g-. of stannous oxide is add d'to 26 g.of the sodium salt of l-o-chlorophenyl2-nitropropane-1,3-dil in 500 cc.of 90% acetic acid. The suspension is stirred at 45 to 55 C. fortwentyfour hours at the end of which time the stannous oxide has for themost part dissolved. The reaction mixture is evaporated to dryness invacuo, the residue dissolved in a small amount of Water and the solutionmade alkaline to pH 11 with sodium hydroxide. The mixture is filtered.the insoluble precipitate extracted about five times with ethyl acetateand the ethyl acetate extracts used to extract the clear filtrate. Theethyl acetate extracts are dried and the ethyl acetate distilled toobtain the unresolved l-o-chlorophenyl-2-aminopropane-l,3-diol as anoil. This product has the formula,

OH NHa I gen-creams Unresolved Crystallization of the oily unresolvedproduct from chloroform yields the crystalline [dll-reg.-1-o-chlorophenyl-Z-aminopropane 1,3 diol, the chloroform solublefraction being predominantly the [GU- ,0 isomer.

Other salts of stannous tin, for example. 70 g. of stannous chloride maybe used in place of the stannous oxide as the reducing agent.

[bl 5 g. of [d1]--1-o-chlorophenyl-2-acetamidopropane-l,3-diol is heatedunder reflux with 100 cc. of 5% hydrochloric acid for one hour. Thereaction mixture is evaporated to dryness in vacuo, the residue taken upin a small amount of water and the solution made alkaline to pH 11 withsodium hydroxide. The solution is extracted with ethyl acetate, theethyl acetate extracts dried and the ethyl acetate distilled to obtainthe desired [dl]-\,b-l-o-chlorophenyl-2-aminopropane-1,3-dio1 offormula,

OH NH:

QeH-eH-omorr [fill-i Form Example 7 shaken under three atmospherespressure of hydrogen for sixteen hours at 25 C. The catalyst is removedby filtration, the filtrate evaporated to dryness in vacuo and theresidue taken up in 5 water. The mixture is extracted with ether, theether extract discarded and the aqueous phase made alkaline to pH withsodium hydroxide. The solution is extracted with five portions of ethylacetate, the e hylacetate extract. dried and 10 the ethyl acetatedistilled to obtain the desired unresolved1-p-methoxyphenyl-2-aminopropane- 1,3-diol of formula,

OH NH:

Unresolved Crystallization of the unresolvedl-p-methoxyphenyl-2-aminopropane-1,3-diol from chloroform yields thechloroform-insoluble, crystalline [d1] -reg.-1-p-methoxyphenyl-2aminopropane- 1,3-diol. The chloroform soluble[dll-w-l-pmethoxyphenyl-2-aminopropane-l,3-diol of formula,

I I omo-OcE-eH-cmori [dll-IP Form is recovered from the chloroformmother liquors by evaporation of the solvent. Purification of thisproduct may be accomplished by further crystallization from chloroformto remove any contaminating [dll-reg. isomer. Purification can also becarried out by converting. the crude [d1] product to the O,N-diacetateby treatment with acetic anhydride at 70 C. for fifteen minutes,recrystallizing the diacetate from ethanol or ethyl acetate to obtainthe pure [d1]- diacetate and hydrolyzing the purified diacetate to thefree amino diol with either alkali or acid.

5 I Example 8' 20 g. of the potassium salt of2-nitro-3-pethylphenyl-butane-l,B-diol in 150 cc. of glacial acetic acidis shaken with 1 g. of palladium oxide 5 hydrogenation catalyst underthree atmospheres pressure of hydrogen for" fifteen hours at 25' C. Thecatalyst is removed by filtration, the filtrate evaporated to dryness invacuo and the residue taken up in water. The mixture is extracted withether, the ether extract discarded and the solution made alkaline to pH10 with sodium hydroxide. The solution is extracted with ethyl acetate,the extract dried and the ethyl acetate distilled to obtain the desiredunresolved Z-amino- 3-p-ethylphenylbutane-1,3-diol of formula,

OH NH:

55 I Ha Unresolved Crystallization of the unresolved 2-amino-3-p-ethylphenylbutane-1,3-diol from chloroform yields as the chloroforminsoluble crystalline fraction the [dll-reg. isomerof-2-amino-3-pethylphenylbutane-l,3-diol. Evaporation of the chloroformmother liquors yields the correspond- 13 Example 9 [a] 5 g. of[d1]-\//-1-p-iodophenyl 2-aeetamidopropane-1,3-dio1 is heated underreflux with 100 cc. of 5% hydrochloric acid for one hour. reactionmixture is evaporated to dryness in vacuo and the residual hydrochloridesalt of [d1] -1- p-iodophenyl-2-aminopropane-1,3-diol taken up in waterand the solution made alkaline to pH .1-0 with sodium hydroxide. Thesolution is extracted With ethyl acetate, the ethyl acetate extractswashed with water, dried and the ethyl acetate distilled in vacuo toobtain the desired free base of [d1]--1-p-iodophenyl-2-aminopropane 1,3-diol of formula,

(GD-i Form [1)] 3 g. of [d1]--1-p-iodophenyl-2-aminopropane-1,3-dioldissolved in a small amount of absolute ethanol is added to an absoluteethanol solution containing a slight excess of [d] -tar'ta1ic acid. Thesolution is concentrated to the point of crystallization in vacuo,chilled and the [d] -tartaric acid salt of[1]-i//-l-p-iodophenyl-Z-aminopropane-1,3-diol which separatescollected. Fractional crystallization of the mother liquors yields the[dl-tartaric acid salt of the [dl-il/ isomer together with an additionalquantity of the [dd-tantaric acid salt of the [ll-il/ isomer. The [d]-tartaric acid salt of [1]-1,b-1-p-iodophenyl-2-aminopropane-1,3-diol isdissolved in a small amount of water, the solution made alkaline to pH10 with sodium hydroxide and extracted with ethyl acetate. The ethylacetate extract is washed with water, dried and the ethyl acetatedistilled to obtain the desired [l]--l-p-iodopheny1-2aminopropane-LB-diol of formula,

OH NH [l]- Form Similarly, neutralization of the idl -tartaric add saltof the ld-l-il/ i'somer yields ld'l-w-l-p-'iodophenylq-aniinopropanel.S-diol.

Example :1 0

g. of Edl]-reg.-l:p ethoxyphenyl fibenzamido-3-benzoyloxypropane 1-ol isheated under reflux with a mixture consisting of 50 cc. of ethanol and50 cc. of 10% hydrobromic acid for three hours. The reaction mixture isevaporated to dryness in vacuo, the residue taken up in water and thesolution made alkaline to pH 10 with sodium hydroxide. 'The solution isextracted with ethyl acetate, the ethyl acetate extract washed withwater, dried and the ethyl acetate distilled to obtain the desiredethoxyphenyl-2- aminopropane l,3diol of -for-. 'mula,

7 I NH: ciHlo QcH cB-=omorr [.dll -Reg. 01211! Example 11 1.5 g. ofpalladium oxide hydrogenation catalyst is added to 20 g. of the sodiumsalt of 1-o- The methoxy-p-methylphenyl 2 nitropropane-1,3- diol "in 125cc. of glacial acetic acid and the resultingmixture shaken under threeatmospheres of hydrogen for fifteen hours at 25 C. The cata lyst isremoved by filtration, the filtrate evaporated to dryness in vacuo andthe residue taken up in water. The solution is extracted with ether, theether extract discarded and the aqueous phase made alkaline to pH 10with sodium hydroxide. The solution is extracted with ethyl acetate, theethyl acetate extract washed with water, dried and the ethyl acetatedistilled in vacuo to obtain the unresolved 1-o-methoxy p=methylphenyl 2am'inopropane-L3-dio1 of formula,

OH NH:

Unresolved Crystallization of the unresolved product obtained above fromchloroform 'y ields as "a crystallin'e fraction the[dll-regwlemethoxy-p- -methylphenyl-2-aminopropane-1,3-diol. Thecorresponding [dl]- isomer is obtained by evapora tion of the chloroformmother liquors.

' Emam'ple :12

157 g. of zinc dust is added to a-mix'ture consisting of 87 g. of thesodium salt' of 1-phenyl-2- nitropropane-1,3-diol, 355 cc. of glacialacetic acid, 250 cc. of ethanol and 400 ccaof water over a period of 45minutes and at a temperature of -'75 C. The reaction *mixture is heatedfor five and one-half hoursgextrac-ted with ether and the ether extractdiscarded. The aqueous phase is made alkaline with sodium hydroxide topH 10 and extracted with five portions of ethyl acetatel The ethylacetate extract is washed with water, dried and evaporated in vacuo toobtain the desired unresolved '1 phenyl 2 aminopropane 1,3-

diol of formula,

. on lTlHz Gen-0343132011 Unresolved In the foregoing examples we haveemployed certain nitro diols and acylated amino diols as startingmaterials. These starting materials can 'beqarepared in a number ofdifferent'ways. One -oiflthe general methods which can be used toprepare the unresolved 'nitro diols consists in con- 'd ensin'g anaromatic "aldehyde or ketone with ac-nitroethanoliin'the presence ofan-a'lkaline condensation catalyst :as shown .in the following equation.

{R1 O alkaline 2H v v condensation ''O;R3 t- NOQ'CHtCHQOH w catalyst 2R1 OH IITO: Dt -eIFcHgOH R2 7 its Unresolved where R1, R2 and R3 havethe same significance -as .given above. The acylated amino dio1 start.-

'ing :materials can be prepared .by the general method shown in thefollowing diagram.

R, I o

@lL-QIbNH-Ac l R2 HC\H [Alkaline condensation catalyst] R1 El) DEE-A0171R1 (i) IIIH-Acyl Do-om-omo-aw 4-- -CHCH10H R1 R2 7 Unresolved UnresolvedR; OH NH-Acyl R1 OH lIIH-Acyl JJHJ7HCHrOAcyl JHCHCH1OH a I UnresolvedUnresolved Separate into struc Separate into structural forms byfractural :orms bv fractional crystallization tional crystallization R(IJH lTIH-Acyl R1 NH-Acyl ;C -CHOH-CEOH Q-oE-n-OEQH R2 k [dH-Reg. formRa [dlH/ Form 7 s R; ()H l |TH-Aoyl R1 (TH NH-Acyl CH-CHCH20Acyl CH(JHCHz0Acyl R2 [dl]-Reg. form R2 [dl]-/ Form i a a a l l O-ACyl NH-Acyl R@c'tn H-CHiO-Acyl R2 [dl]-Reg. form R2 where R1 and R2 have the samesignificance as given above. r

The following examples serve to illustrate the application ofthesegeneral methods to the preparation of some of the specific startingmaterials used in the foregoing examples.

Example 13 1.1 g. of sodium is dissolved in 20 cc. of methanol and theresulting solution added to a solution of g. of benzaldehyde and 4.5 g.of B-nitroethanol in cc. of methanol. After standing at room temperaturefor a short time the gel which forms on the mixing of the reactantschanges to a white insoluble powder. The precipitate is collected,washed with methanol and ether and then dried. The product thus produoedis the sodium salt of I-phenyl-Z-nitropropane-1,3-diol. If desired, thefree nitro-diol having the formula,

OH N02 raham Unresolved can be obtained byacidification of the salt.

- Example 14 I 2.2' g. of sodium dissolved in 40 cc. of methanol isadded to a solution of 12 g. of o-methyl benzaldehyde and 9 g. of,B-nitroethanol in 40 cc. of

CH-CHaO-Acyl [dlH/ Form methanol. The reaction mixture is allowed tostand at room temperature for a short time and then the white insolublesodium salt of l-o-methylphenyl-2-nitropropane-1,3-diol removed byfiltration, washed with ether and dried. Acidification of this sodiumsalt produces the corresponding free nitro compound, 1-o-methylpheny1-2-nitropropane-1,3-diol, which has the formula,

OH N02 Unresolved Example 15 16.2 g. of sodium is dissolved in 300 cc.of methanol and the solution added to a mixture consisting of 96 g. ofanisaldehyde and g. of fl-nitroethanol in 250 cc. of methanol at 5 C.The reaction mixture is allowed to stand for two hours and then thewhite insoluble sodium salt of l-p-methoxyphenyl 2--nitropropane-1,3-diol collected, washed withether and dried.Acidification of this salt producesthe free nitro compound,l-p-methoxyphenyl-2-nitropropane-l,3- diol of formula,

HOH 'NO2 Unresolved Example 16 The nitro diol starting materials havingthe formula,

on N02 Unresolved can, be prepared by starting withSgt-dimethylbenzaldehyde and p-nitroethanol and following the proceduresdescribed in Examples 13, 1e and 115.

Example 17 The nitro diol compounds; used as starting materials in thepreparation of the amino diols having the general formula,

OH NH2 stn crnon 933 V are prepared by starting with acetophenone andc-nitroethanol and following the procedures described in Examples 13, 14and 15,

Example 18 The nitro diol products used as starting materials having theformula,

OH B1102 Ottawa-onion Unresolved can be prepared fromo-chlorobenzaldehyde and p-nitroethanol using the; procedures describedin Examples 13, Hand 15.

Example 19 A mixture consisting of 4 8g. of'w-benzoylaminoacetophenone,7.2 g. of paraformaldehyde and 0.2 g. of potassium carbonate in 300 cc.of methanol is allowed to stand at room temperature for eighteenminutes. The reaction mixture is added to one liter of ice water and thegummy solid which separates collected and washed with water. The crudea-benzamido-B-hydroxypropiophenone,

NHC

thus obtained is dissolved in 400 cc. of ethanol. g. of Raney. nickel isadded to the solution and the mixture shaken with gaseous hydrogen underabout 50 lbs. per sq. in. pressure for three to four hours at roomtemperature. The catalyst is removed by filtration and the filtrateheated to boiling and mixed with an equal volume of hot water. Afterallowing the cool solution contairu ing the desired1-phenyl-2-benzamidopropane- 1,3-dio1 to stand overnight at 0 C., thecrystals which have separated from the solution are collected. Thiscrystalline product is the pseudo or trans structural form of thedesired benzamido diol, [dl]-11-1-phenyl-2-benzamidopropane-1,3- diol.The formula of this product which melts at 166 -7 C. afterrecrystallization from ethanol is,

18 The filtrate from the separation of the [dll-zl/ form of the productis evaporated to dryness in vacuo and the crude reg. or cis structuralform of the benzamido diol purified by recrystallization from methanol.Its formula is,

[dl]-Reg. form 8 g. of a-benzamido-c-hydroxypropiophenone is heated atabout 75 C. for one-half hour with 20 cc. of acetic anhydride containinga small amount of concentrated sulfuric acid and then the reactionmixture evaporated to dryness in vacuo. The residual crudem-benzamido-B- acetoxypropiophenone is washed with. ice water andpurified by recrystallization from methanol or ethanol. Its formula is:

A mixture consisting of 10 g. of a-benzamido-fi acetoxypropiophenone,0.3 g. of Raney nickel hydrogenation catalyst and 150 cc. of methanol isshaken at 30 C. with gaseous hydrogen under a pressure of about 60 lbs.per sq. in. until thetheoretical amount of hydrogen has been absorbed.The reaction mixture. is concentrated to a volume of about cc. in vacuo,cooled and the catalyst and insoluble organic material removed byfiltration. The solid is extracted with boiling alcohol, the extractscooled and the crude [fill-girlphenyl-Z-benzamido 3 acctoxypropane l o1collected, This product which hasthe formula,

oni o OE? n-cmod-om [1111-111 Form can be purified further if desired byrecrystallization from alcohol.

The corresponding [dll-reg isomercan be obtained from the filtrate ofthe reaction mixture by evaporation of the methanol. The pure isomer isobtained by recrystallization of the crude material from alcohol-watermixtures.

3 g. of [d1]-1,b-1-phenyl 2-bnzamidopropane- 1,3-di01 is heated with 10cc. of acetic anhydride at 70 C. for fifteen minutes and then thereaction mixture is evaporated to dryness in vacuo. Recrystallization ofthe residue from ethanol yields the desired [(11]1/-1-phenyl-2benzamido- 3 -acetoxypropane1-ol, in crystalline form. Theformula of this product is,

I O on o Gen-01141120, tLon;

2 g; of [dl] 0-1-phenyl-2-benzamidopropane- 1-,3-diol is added to amixture composed of 4 cc. of acetic anhydride and 4 cc. of dry pyridine19 and the resulting mixture heated at 106 C. for about one-half hour.The reaction mixture is evaporated to dryness in vacuo and the residuecrystallized from methanol to obtain the desired [d1] 1// 1 phenyl 2benzainido-l,3-diacet oxypropane of formula,

If desired, an equivalent amount of [d1] \//-1-phenyl-2-benzamido-3-acetoxypropane-l-ol can be substituted for theN-benzoyl derivative used in the above procedure.

Example 20 0.2 g. of sodium bicarbonate is added to a solution of 17.7g. of w-acetylaminoacetophenone and 6 g. of paraformaldehyde in 300 cc.of methanol and the resulting mixture heated at 45 to 50 C. for aboutone-half hour. The reaction mixture is poured into 800 cc. of ice waterand the crude a-acetamido-fi-hydroxypropiophenone which separatescollected and washed with water. If desired, this product can bepurified by recrystallization from methanol. Its formula is,

3 g. of Raney nickel hydrogenation catalyst is added to a solution of 15g. of a-acetamidm B-hydroxypropiophenone in 200 cc. of ethanol and themixture shaken with gaseous hydrogen under a pressure of about 60 lbs.per sq. in. at 30 C. until one mol of hydrogen has been ab sorbed. Thecatalyst is removed by filtration,

the filtrate containing the desired l-phenyl-2-acetamidopropane-1,3-diol heated to boiling and treated with slightlymore than an equal volume of hot water.- After standing at C. for abouttwenty-four hours, the crystalline [d1]0-1-phenyl-Z-acetamidopropane-1,3 diol is collected and purified byrecrystallization from methanol; M. P. 132-3 C. This product has theformula,

OdH-dir- H2OH [dB-1,0 Form The filtrate from the separation of the [dB-0 isomer is evaporated to dryness in vacuo and the residue whichconsists principally of the [dll-reg. isomer purified by fractionalcrystallization from ethanol or ethanol-water mixtures to obtain thepure [d1]-reg.-l-phenyl-2-acet amidopropane-lj -diol. The formula ofthis product is the same as that of the [sill-,0 isomer except that thiscompound has a cis structural configuration.

A mixture consisting of 5 g. of u-acetamido- ,B-hydroxypropiophenone andcc. of acetic anhydride is warmed to 40 C. and one drop of concentratedsulfuric acid, added to the solution. The mixture is allowed to standfor one-half hour and then is evaporated to dryness in vacuo.

20 The residue which consists of a-acetamido [3-acetoxypropiophenone offormula,

' QE-lH-CEEOE-CH:

- is washed with water and purified by recrystallization from ethanol.

A mixture consisting of 20 g. of a-acetamido- ,B-acetoxypropiophenone,0.5 g. of Raney nickel hydrogenation catalyst and 200 cc. of ethanol isshaken at 25 C. with gaseous hydrogen under a pressure of about 50 lbs.per sq. in. until one mol of hydrogen has been absorbed. The reactionmixture is chilled and the solid removed by filtration. The solid whichconsists of a mixture of [d1]b-l-phenyl-Z-acetamido-3-acetoxypropane-l-ol and the hydrogenationcatalyst is extracted with boiling ethanol, the extracts cooled and the[d1]-/-1-phenyl-2-acetamido- 3-aeetoxypropane-1-0l which separatescollected. This compound which has the formula,

on OdHQiEPGILO-C-Om Example 21 A mixture consisting of 25.3 g. ofw-benzoylamino-2-methylacetophenone, 6g. of paraformaldehyde and 0.3 g.of pyridine in 300 cc. of ethanol is warmed at 35 C. for one-half hourand then poured into 800 cc. of ice water. The crudea-benzamido-p-hydroxy 2 methylpropiophenone is collected, washed withwater and purified by recrystallization from methanol. The formula ofthis product is:

i l Qc- ,H-omoH 0.5 g. of palladium oxide hydrogenation catalyst isadded to a solution of 20 g. ofa-benzamidof3-hydr0xy-Z-methylpropiophenone in 300 cc. of ethanol andthe mixture shaken at room temperature with gaseous hydrogen under apressure of about 50 lbs. per sq. in. until one mol of hydrogen has beenabsorbed. The catalyst is removed by filtration, the filtrate containingthe desired 1 [2' methylphenyll 2 benzamidopropane-1,3-diol concentratedto a volume of about cc. and an equal volume of hot water added to thehot solution. After allowing the solution to stand at 0 C. for abouttwenty-four hours, the crystalline [d1]-1p-l-[2-methylphenyl]-2-benzamidooropane-1,3-diol is collected andpurified by recrystallization from methanol. Its formula is,

[dl]-il Form The filtrate from which the [dll isomer has been separatedis evaporated to dryness and the residue taken up and fractionallycrystallized from methanol to obtain the desired [dll-reg-l- [2-methylphenyll 2 benzamidopropane 1,3-

diol of formula,

0 OH I G-llEL-CH-CHNH lHs [GU-Reg. form R1 OH NH? De Ra Ra where R1 andR2 are members of the class consisting of hydrogen, halogen, lower alkyland lower alkoxy radicals and R3 is a member of the class consisting ofhydrogen and lower alkyl radicals.

2. A compound of the class consisting of an amino diol and its acidaddition salts, said amino diol having the formula,

OH NH:

Gr m-( nventor:

3. A compound of the formula,

OH NHi 4. A compound of the formula,

OH NHz I O-dn-cn-cmon (GD-1,0 Form 5. A compound of the class consistingof an amino diol and its acid addition salts, said amino diol having theformula,

I IGOR-JJH-CILOH 6. A compound of the formula,

OH NH:

I IOCH-dH-CEOH 7. A compound of the formula,

OH NH! IOJJH H-CH2OH [1]-',0 Form 8. A compound of the class consistingof an amino diol and its acid addition salts, said amino diol having theformula,

OH NH:

I l omoGcn-on-cmon 9. A compound of the formula,

OH NH:

10. A compound of the formula,

OH NH:

| I CHgO-OGH-CH-CHNH HARRY M. CROOKS}. JR. MILDRED C. REBSTOCK. JOHNCONTROULIS. QUENTIN BARTZ.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,103,266 Lott Dec. 28, 19372,363,465 Senkus Nov. 21, 1944 OTHER REFERENCES Cherbuliez et a1;Chemical Abstracts, vol. 25, p. 2132 (1931).

Degering: Organic Nitrogen Cpds., (Univ.

Lithoprinters, Ypsilanti, Mich., 1945), pp. 409,

1. A COMPOUND OF THE CLASS CONSISTING OF AN AMINO DIOL AND ITS ACIDADDITION SALTS, SAID AMINO DIOL HAVING THE FORMULA,